Adverse events and treatment discontinuations in clinical trials of fluoxetine in major depressive disorder: An updated meta-analysis

Background: A 1993 meta-analysis of US Investigational New Drug clinical tr ials of fluoxetine reinforced this agent's more favorable adverse-event pro file compared with tricyclic antidepressants (TCAs). Objectives: The present meta-analysis sought to provide a reanalysis of upd ated adverse-event and discontinuation data for fluoxetine 20 to 80 mg/d co mpared with TCAs and placebo in the treatment of major depressive disorder (MDD) in adults. A subanalysis to assess the safety profile of the most com monly used effective dose of fluoxetine in MDD (20 mg) was also conducted. Methods: Data were obtained from 25 double-blind clinical trials involving 4016 patients with MDD randomized to treatment with fluoxetine 20 to 80 mg/ d, TCAs, or placebo. The subanalysis included data from 6 trials involving 1258 patients treated with fixed 20-mg doses of fluoxetine or placebo. Spon taneously reported treatment-emergent adverse events, reasons for discontin uation, and events leading to discontinuation were compared between groups. Results: The age of the 4016 randomized patients ranged from 12 to 90 years , with a mean age of 46 years. Most patients were white (92%), and 62% were female. The age of the 1258 patients in the 20-mg fixed-dose population ra nged from 18 to 90 years, with a mean age of 54 years; as in the total popu lation, most of these patients were white (92%), and 57% were female. The a dverse-event profiles of fluoxetine and TCAs in these trials were consisten t with the typical profiles of selective serotonin reuptake inhibitors and TCAs. At a dose of 20 mg/d, fluoxetine-treated patients had a discontinuati on rate due to adverse events that was not statistically significantly diff erent from that in placebo recipients. Discontinuation rates due to lack of efficacy were not significantly different between fluoxetine and TCAs. How ever, significantly more TCA-treated patients discontinued therapy because of adverse events and significantly fewer completed treatment compared with fluoxetine-treated patients (both, P < 0.001). The most common events (<gr eater than or equal to>2%) leading to discontinuation were asthenia, dizzin ess, insomnia, nausea, nervousness, somnolence, and tremor in fluoxetine-tr eated patients and abnormal vision, agitation, constipation, dizziness, dry mouth, headache, nausea, nervousness, rash, somnolence, sweating, and trem or in TCA-treated patients. Conclusions: Data from this large series of clinical trials confirm that fl uoxetine is well tolerated in the acute treatment of MDD in adults, especia lly at a dosage of 20 mg/d, and is better tolerated than the recommended do ses of TCAs.